The prevalence of heart failure (HF) is increasing, mainly due to population aging. There are important biological (sex) and sociocultural (gender) differences in epidemiology, pathophysiology, phenotype, prognosis, and treatment of HF between women and men. While the overall lifetime risk of HF is similar between men and women, women with HF are older, have more comorbidities, and a higher incidence of heart failure with preserved ejection fraction (HFpEF) than men. Men instead present a predisposition to the development of heart failure with reduced ejection fraction (HFrEF) due to their higher incidence of coronary artery disease. Sex differences are also notable in the penetrance of genetic cardiomyopathies, HF risk factors as well as in sex-specific conditions such as peripartum cardiomyopathy (PPCM), cancer treatment-induced cardiomyopathy, and Takotsubo cardiomyopathy. Although women with HF have a better age-adjusted prognosis than men, they experience worse quality of life. Underpinning current sex disparities in HF, HF treatment is limited by a profound underrepresentation of women in clinical trials, which has resulted in a lesser understanding of disease behaviour in female patients and in treatment guidelines that are predominantly based on male-derived data. In addition, a full understanding of the impact of sociocultural gender on HF management and disease course is lacking. This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address existing knowledge gaps in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy and heart transplantation.